Alzheimer's disease is a neurodegenerative disease of the brain leading to severely impaired cognition and functionality. This disease leads to progressive regression of memory and learned functions. Alzheimer's disease is a complex disease that affects cholinergic neurons, as well as serotonergic, noradrenergic and other central neurotransmitter systems. Manifestations of Alzheimer's disease extends beyond memory loss and include personality changes, neuromuscular changes, seizures, and occasionally psychotic features.
The defining pathological hallmarks of AD are the presence of neurofibrillary tangles and senile plaques in the brain. Amyloid β polypeptides (AP) are the major constituents of amyloid plaques and are derived from altered processing of amyloid precursor proteins (APPs). Aβ consists predominantly of two forms, Aβ40 and Aβ42. Although Aβ40 is the predominant form, recent evidence suggests that Aβ42 is the pathogenic form. In addition to Aβ40 and Aβ42, the processing of Aβ generates other Aβ forms such as Aβ39, Aβ38, Aβ37, and Aβ34.
The present invention encompasses geminally di-substituted derivatives of nonsteroidal anti-inflammatory drugs, which lower the level of Aβ42 and are therefore useful for preventing, delaying or reversing the progression of Alzheimer's Disease. The compounds of the invention also have a reduced potency for cyclooxygenase activity and therefore do not possess the gastrointestinal side effects associated with nonsteroidal antiinflammatory drugs (NSAIDs).